The compound 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula-I and its hydrochloride salt having international non proprietary name as tapentadol hydrochloride is a centrally-acting analgesic with a dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor.
The compound was first time disclosed in patent EP0693475; wherein 3-bromo anisole of Formula-II is reacted with 1,1-dimethylamino-2-methylpentan-3-one of Formula-III under conditions of Grignard reaction to obtain racemic 1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride of Formula-IV. The compound of Formula-IV is converted to its base and subjected to enantiomeric separation using chiral HPLC column to obtain (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol of Formula-V, which on chlorination using thionyl chloride forms (2S,3R)-3-chloro-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine of Formula-VI. The compound of Formula-VI on reaction with zinc borohydride or tin cyanoborohydride results in the formation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine of Formula-VII. The compound of Formula-VII on heating with concentrated hydrobromic acid results in the compound 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula-I. Throughout the reaction the intermediate salt formation wherever required and final hydrochloride salt preparation is done using trimethylchloro silane The reaction sequence is as represented in scheme-1 below.

The drawback of the above invention is the use of chiral HPLC column to separate the required enantiomer and use of trimethylchloro silane for preparation of hydrochloride salt which renders the process industrially uneconomical.
WO2004/108658 ('658) describes process for the preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine of Formula-VII, the penultimate intermediate to prepare tapentadol, wherein the compound (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol of Formula-VA, is heated in acidic medium to get intermediate compound (Z,E)-(S)-[3-(3-methoxyphenyl)-2-methyl-pent-3-enyl]-dimethylamine HCl of Formula-X, which on catalytic hydrogenation yields enantiomeric mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine of Formula-VII and (2R,3S))-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine of Formula-VIIA. The required stereoisomer is separated to get (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine of Formula-VII, which can be treated with concentrated hydrobromic acid to get tapentadol. The reaction sequence is as per scheme-2 below;

WO2005/000788 ('788) describes another method of preparing tapentadol, wherein compound (2S,3S)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pentanol of Formula-VA is subjected to dehydration reaction using heterogeneous catalyst to get intermediate compound (Z,E)-(S)-[3-(3-methoxyphenyl)-2-methyl-pent-3-enyl]-dimethyl amine hydrochloride of Formula-X, which on catalytic reduction yields enantiomeric mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine of Formula-VII and (2R,3S))-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine of Formula VIIA The required stereoisomer is separated to get (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine Formula-VII.
The drawback of the above invention as disclosed in '658 and '788 is the formation of mixtures of distereoisomer (2R,3R)-3-(3-methoxyphenyl)-N,N,2 trimethylpentan-1-amine and (2R,3S)-3-(3-methoxyphenyl)-N,N,2 trimethylpentan-1-amine during the preparation which requires separation of the required stereoisomer resulting in lower yield and the unwanted isomer is left as it is thus affecting the economy of the process.
WO2008/012046 describes another method for the preparation of tapentadol, wherein 1-(3-(benzyloxy)phenyl)propan-1-one is reacted with N-Methyl-N-methylene-methaneaminium chloride in presence of acetyl chloride and solvent acetonitrile to obtain compound 1-(3-(benzyloxy)phenyl)-3-(dimethylamino)-2-methylpropan-1-one. The compound is resolved with L-(−)-dibenzoyltartaric acid to get (S)-1-(3-(benzyloxy)phenyl)-3-(dimethylamino)-2-methylpropan-1-one. The isolated compound is then reacted with ethyl magnesium bromide undergoing Grignard reaction to isolate (2S,3R)-3-(3-(benzyloxy)phenyl)-1-(dimethylamino)-2-methylpentan-3-ol, which on reaction with trifluoroacetic anhydride in acetic acid results in acetylated compound. The acetylated compound on hydrogenolysis results in the compound 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula-I.
The drawback of the above invention involves in use of costly reagent and solvents trifluoroacetic anhydride for acetylation of alcoholic —OH group and acetonitrile solvent for the condensation reaction affecting economy of the process on industrial scale.
WO2008012047 describes yet another method for the preparation of tapentadol, wherein 1-(3-methoxyphenyl)propan-1-one is reacted with dimethyl amine hydrochloride and paraformaldehyde under Mannich reaction condition to get 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one hydrochloride, which after reacting with sodium hydroxide is reacted with (2R,3R)—O,O′-dibenzoyl tartaric acid monohydrate to get (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one L-(−)-dibenzoyltartarate. The dibenzoyl tartrate salt is further reacted with diethyl amine to isolate keto compound (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one. The keto compound is reacted with ethyl magnesium halide under Grignard condition to isolate the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol. The hydrochloride salt of the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol on reaction with aqueous hydrochloric acid undergoes dehydration yielding the compound (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine, which after hydrogenation using homogeneous or heterogeneous catalyst results in the mixture of compound (2R,3R))-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine having Z:E ratio of 5.5:1. The required compound (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine is separated from the mixture by making hydrochloride salt. The isolated salt is dissolved in methane sulphonic acid and treated with methionine to get the compound 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula-I, which is isolated as hydrochloride salt of tapentadol hydrochloride.
The drawbacks of the above process are,                i. resolution of the racemic intermediate using chiral reagent increases the reaction steps;        ii. mixtures of distereoisomer require resolution and separation of the required stereoisomer resulting in lower yield and the unwanted isomer is left as it is affecting the economy of the process.        
Therefore, there remains a need for an improved process for preparing the compound 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula-I that eliminates or substantially reduces the number of steps, overcomes resolution and separation of stereoisomer, avoids chromatographic separation of required enantiomer and employs safe and economical reagents for the reaction.
Thus, the present inventors have come out with an improved process which ameliorates the problems in the prior art by using a stereospecific reaction conditions to avoid the resolution, and carrying out chemical purification thus avoiding the chromatographic separation of the required enantiomer and use of catalyst for reductive deoxygenation to improve safety and cleaner reaction.